30
Asymmetric Synthesis of Three-Membered Rings
Asymmetric Synthesis of Three-Membered Rings
Hélène Pellissier, Alessandra Lattanzi and Renato Dalpozzo
Authors
Dr. Hélène PellissierAix Marseille UniversitéInstitut des Sciences Moléculaires de MarseilleUMR CNRS 7313 Avenue Escadrille Normandie-Niemen13397 MarseilleFrance
Professor Alessandra LattanziUniversità di SalernoDipartimento di Chimica e Biologia A. ZambelliVia Giovanni Paolo II84084 FiscianoItaly
Professor Renato DalpozzoUniversità della CalabriaDipartimento di Chimica e Tecnolgie ChimichePonte Bucci, Cubo 12/C87036 Arcavacata di Rende (CS)Italy
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v
Contents
Preface ixList of Abbreviations xi
1 Asymmetric Cyclopropanation 11.1 Introduction 11.2 Simmons–Smith Cyclopropanation 21.2.1 Chiral Substrates 31.2.1.1 Chiral Allylic Alcohols 31.2.1.2 Chiral Allylic Amines 71.2.1.3 Chiral Acetal-Directed Cyclopropanations 71.2.1.4 Simple Chiral Alkenes 91.2.2 Chiral Auxiliaries 111.2.3 Chiral Catalysts 151.2.3.1 Charette’s Ligand 151.2.3.2 Other Stoichiometric Ligands 201.2.3.3 Walsh’ Procedure 221.2.3.4 True Catalytic Procedures 241.3 Transition-Metal-Catalyzed Decomposition of Diazoalkanes 271.3.1 Intermolecular Cyclopropanation 281.3.1.1 Chiral Auxiliaries 281.3.1.2 Chiral Catalysts: Cobalt 321.3.1.3 Chiral Catalysts: Copper 381.3.1.4 Chiral Catalysts: Rhodium 561.3.1.5 Chiral Catalysts: Ruthenium 691.3.1.6 Chiral Catalyst: Other Metals 771.3.2 Intramolecular Cyclopropanation 801.3.2.1 Chiral Auxiliaries and Chiral Compounds 801.3.2.2 Chiral Catalysts 821.3.3 Chiral Stoichiometric Carbenes 931.4 Michael-Initiated and Other Ring Closures 941.4.1 Chiral Substrates 951.4.2 Chiral Auxiliaries 1001.4.2.1 Chiral Michael Acceptors 1001.4.2.2 Chiral Nucleophiles 106
Contentsvi
1.4.3 Organocatalysis 1151.4.3.1 Ylides 1161.4.3.2 Nitrocyclopropanation 1181.4.3.3 Halocarbonyl Compounds 1281.4.4 Metal Catalysis 1391.4.5 Other Ring Closures 1401.5 Miscellaneous Reactions 1481.5.1 Rearrangement of Chiral Oxiranes 1481.5.2 Cycloisomerization of 1,n-Enynes 1521.5.3 Denitrogenation of Chiral Pyrazolines 1601.5.4 C–H Insertion 1621.5.5 Addition to Cyclopropenes 1641.5.6 Other Methods 1671.6 Conclusions 172 References 172
2 Asymmetric Aziridination 2052.1 Introduction 2052.2 Aziridination Based on the Use of Chiral Substrates 2062.2.1 Addition to Alkenes 2062.2.1.1 Aziridination via Nitrene Transfer to Alkenes 2062.2.1.2 Aziridination via Addition–Elimination Processes 2192.2.1.3 Miscellaneous Reactions 2242.2.2 Addition to Imines 2252.2.2.1 Methylidation of Imines 2262.2.2.2 Aza-Darzens and Analogous Reactions 2482.2.2.3 Addition/Elimination Processes 2552.2.2.4 Miscellaneous Reactions 2662.2.3 Addition to Azirines 2672.2.4 Aziridination via Intramolecular Substitution 2702.2.4.1 From 1,2-Amino Alcohols 2702.2.4.2 From 1,2-Amino Halides 2782.2.4.3 From 1,2-Azido Alcohols 2822.2.4.4 From 1,2-Amino Sulfides and 1,2-Amino Selenides 2852.2.4.5 From Epoxides 2862.2.5 Miscellaneous Reactions 2872.3 Aziridination Based on the Use of Chiral Catalysts 2962.3.1 Aziridination via Nitrene Transfer to Alkenes 2962.3.1.1 Cu-Catalyzed Aziridination 2962.3.1.2 Rh-Catalyzed Aziridination 3102.3.1.3 Ru-Catalyzed Aziridination 3122.3.1.4 Catalysis by Other Metals 3142.3.1.5 Organocatalyzed Aziridination 3182.3.2 Aziridination via Carbene Transfer to Imines 3322.3.2.1 Carbene Methodology 3322.3.2.2 Sulfur-Ylide-Mediated Aziridination 350
Contents vii
2.3.3 Miscellaneous Reactions 3532.3.4 Kinetic Resolutions of Aziridines 3572.4 Conclusions 363 References 364
3 Asymmetric Epoxidation 3793.1 Introduction 3793.2 Asymmetric Epoxidations Based on the Use
of Chiral Auxiliaries 3803.3 Asymmetric Metal-Catalyzed Epoxidations 3813.3.1 Ti-, Zr-, Hf-Catalyzed Epoxidations 3813.3.2 V-, Nb-, Ta-Catalyzed Epoxidations 3913.3.3 Cr-, Mo-, W-Catalyzed Epoxidations 3973.3.4 Mn-, Re-, Fe-, Ru-Catalyzed Epoxidations 4003.3.5 Pt-, Zn-, Lanthanoid-Catalyzed Epoxidations 4123.4 Asymmetric Organocatalyzed Epoxidations 4193.4.1 Phase-Transfer Catalyst 4193.4.2 Polyamino Acids and Aspartate-Derived Peracids 4233.4.3 Chiral Dioxiranes, Iminium Salts, and Alkyl Hydroperoxides 4313.4.4 Chiral Amines 4473.5 Kinetic Resolution of Racemic Epoxides 4683.6 Asymmetric Sulfur-Ylide-Mediated Epoxidations 4803.7 Asymmetric Darzens-Type Epoxidations 4893.7.1 Chiral Auxiliary- and Reagent-Mediated Darzens Reactions 4893.7.2 Catalytic Asymmetric Darzens Reactions 4923.8 Other Ylide-Mediated Epoxidations 5033.9 Asymmetric Biocatalyzed Synthesis of Epoxides 5053.10 Conclusions 512 References 514
4 Asymmetric Oxaziridination 5394.1 Introduction 5394.2 Oxaziridination Using Chiral Substrates 5404.3 Oxaziridination Using Chiral Catalysts 5444.4 Kinetic Resolutions 5514.5 Conclusions 554 References 555
5 Asymmetric Azirination and Thiirination 5595.1 Introduction 5595.2 Asymmetric Azirination 5595.2.1 Neber Approaches 5605.2.2 Elimination Approaches 5655.2.3 Other Approaches 5695.3 Asymmetric Thiirination 5705.3.1 Conversion of Epoxides 571
Contentsviii
5.3.2 Condensation of Sulfur‐Stabilized Carbanions to Carbonyl Compounds 572
5.3.3 Intramolecular Nucleophilic Substitution 5745.3.4 Miscellaneous Reactions 5765.4 Conclusions 577 References 579
Index 583
ix
The importance of chirality is well recognized related to the fact that nearly all natural products are chiral and their physiological or pharmacological properties depend upon their recognition by chiral receptors, which will interact only with molecules of the proper absolute configuration. Indeed, the use of chiral drugs in enantiopure form is now a standard requirement for virtually every new chemi-cal entity, and the development of new synthetic methods to obtain enantiopure compounds has become a key goal for pharmaceutical companies. Asymmetric synthesis constitutes one of the main strategies to gain access to enantioenriched compounds, involving the use of either chiral auxiliaries or catalysts.
Even 134 years after the synthesis of the first cyclopropane derivative, the syn-thesis of chiral three‐membered (hetero)cycles remains a considerable challenge. Their strained structures, interesting bonding characteristics, and value as an internal mechanistic probe have attracted the attention of the physical organic chemistry community. Moreover, organic chemists have always been fascinated by these subunits, which have been playing a prominent role in organic chemis-try. In fact, while three‐membered rings are highly strained entities, they are nonetheless found in a wide variety of naturally occurring compounds including terpenes, pheromones, fatty acid metabolites, and unusual amino acids, among others. Indeed, the prevalence of three‐membered‐containing (hetero)com-pounds with biological activity, whether isolated from natural sources or ration-ally designed pharmaceutical agents, has inspired chemists to find novel and diverse approaches to their synthesis. The main strategy to gain access to these enantioenriched compounds involve the use of either chiral auxiliaries or cata-lysts that can in turn be metal‐centered, small organic asymmetric molecules or enzymes.
This book collects all the developments achieved in the last 12 years in the fields of asymmetric cyclopropanation, aziridination, epoxidation, oxaziridina-tion, azirination, and thiirination reactions. In addition to describing the large number of highly efficient processes based on the use of various chiral auxiliaries or substrates, this book demonstrates that the most important achievements in asymmetric synthesis of three‐membered rings are the spectacular expansion of novel chiral catalysts, including the especially attractive chiral organocatalysts, which have been recently applied to these reactions. Indeed, a collection of new chiral Lewis‐acid catalysts and organocatalysts have provided new opportunities for these enantioselective reactions and widely expanded their scope.
Preface
Prefacex
Each chapter of the book covers issues related to the title reactions and includes selected applications of the multiple synthetic methodologies discussed to prepare pharmaceuticals, natural or biologically active compounds. All the chapters include synthetic procedures based on the use of chiral pools and auxiliaries, which were employed in the earlier times, but also more convenient catalytic approaches based on the use of chiral metal catalysts and more recently organocatalysts.
Chapter 1, by R. Dalpozzo, deals with the synthesis of chiral cyclopropanes through asymmetric cyclopropanation. The more efficient methodologies employed are the well‐known Simmons–Smith reaction, the transition‐metal‐catalyzed decomposition of diazo compounds, and the irreversible Michael‐initiated ring clo-sure (MIRC), among others. For all these procedures, the use of chiral substrates or auxiliaries as well as that of chiral metal‐ and organocatalysts is covered.
Chapter 2, by H. Pellissier, collects the recent developments in asymmetric aziridination. The use of chiral substrates in addition reactions to alkenes, imines, and azirines as well as in intramolecular substitutions among other reactions is developed in a first section. The second section deals with enantioselective metal‐ and organocatalyzed carbene transfers to imines and nitrene transfers to alkenes along with catalytic kinetic resolutions of racemic aziridines among other reac-tions promoted by chiral catalysts of all types.
Chapter 3, by A. Lattanzi, demonstrates the important progress achieved in the past decade in the vast area of asymmetric synthesis of epoxides. Important enantioselective metal‐ and organocatalyzed epoxidations of alkenes are firstly covered, while other sections deal with kinetic resolution of racemic epoxides, asymmetric sulfur‐ylide‐mediated epoxidations of carbonyl compounds, asym-metric Darzens reactions, and biocatalyzed synthesis of epoxides, among other methodologies.
Chapter 4, by H. Pellissier, deals with asymmetric oxaziridination, which can be achieved by using chiral substrates or chiral catalysts and kinetic resolutions. It is the smallest chapter of the book, demonstrating that this field is still in its infancy because it has been overshadowed for a long time by the fact that elec-tron‐deficient oxaziridines can be employed as convenient and stable sources of electrophilic oxygen.
Chapter 5, by H. Pellissier, collects the advances in asymmetric azirination and thiirination using chiral reagents as well as chiral catalysts, focusing on those published in the last 12 years.
The authors hope that this book will provide an insight into the present stage of asymmetric synthesis of three‐membered rings and stimulate chemists to future discoveries to fulfill the enormous potential in this area, opening the way to the synthesis of a number of important products.
xi
2,6‐DCPNO 2,6‐dichloropyridine N‐oxideacac acetylacetonateACDC asymmetric counteranion‐directed catalysisAd 1‐adamantylAKR aminolytic kinetic resolutionAnth anthrylAr arylBARF tetrakis(3,5‐bis(trifluoromethyl)phenyl)borateBHT 2,6‐di‐t‐butyl‐4‐methylphenylBINAM 1,1′‐binaphthyl‐2,2′‐diamineBINAP 2,2′‐bis(diphenylphosphino)‐1,1′‐ binaphthylBINOL 1,1′‐bi‐2‐naphtholBMEH Bacillus megaterium epoxide hydrolaseBn benzylBoc tert‐butoxycarbonylBox bis(oxazoline)Bs benzenesulfonylBt benzotriazoleBUDAM tetra‐tert‐butyldianisylmethylBz benzoyl (PhCO)CAN ceric ammonium nitrateCBS oxazaborolidine Corey–Bakshi–Shibata catalystCbz benzyloxycarbonylCHP cumyl hydroperoxideCod 1,5‐cyclooctadieneCp cyclopentadienylCPO chloroperoxidaseCSA camphorsulfonic acidCy cyclohexylDABCO 1,4‐diazabicyclo[2.2.2]octaneDAM dianisylmethylDAP diaminopimelic acidDBN 3,5‐dinitrobenzoylDBU 1,5‐diazabicyclo[5.4.0]undec‐5‐eneDCC N,N′‐dicyclohexylcarbodiimide
List of Abbreviations
List of Abbreviationsxii
DCE 1,2‐dichloroethanede diastereomeric excessDEAD diethyl azodicarboxylateDec decylDFT density functional theoryDIAD diisopropyl azodicarboxylateDIC diisopropylcarbodiimideDIPEA diisopropyl ethyl amineDMAP 4‐(N,N‐dimethylamino)pyridineDMD dimethyl dioxiraneDME dimethoxyethaneDMF N,N‐dimethylformamideDMM dimethoxymethaneDMPU 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinoneDMSO dimethylsulfoxideDNA deoxyribonucleic acidDPPA diphenylphosphoryl azidedr diastereomeric ratioE electrophileEDA ethyl diazoacetateee enantiomeric excessEH epoxide hydrolaseEPR electron paramagnetic resonanceESI‐MS electrospray ionization–mass spectrometryEsp α,α,α′,α′‐tetramethyl‐1,3‐benzenedipropionateEWG electron‐withdrawing groupFAD flavin adenine dinucleotideFG functional groupFu furylGDH glucose dehydrogenaseHDHH halohydrin dehalogenaseHept heptylHex hexylHKR hydrolytic kinetic resolutionHMDS hexamethyldisilazideHMPA hexamethylphosphoramineJHC Jørgensen–Hayashi catalystKSAE Katsuki–Sharpless asymmetric epoxidationL ligandLA Lewis acidLDA lithium diisopropylamideLDHs layered double hydroxidesl‐DET l‐diethyl tartratel‐DIPT l‐diisopropyl tartrateLEH limonene 1,2‐epoxide hydrolaseLG leaving groupLIDAKOR lithium diisopropylamide‐potassium t‐butoxide
List of Abbreviations xiii
LTMP lithium 2,2,6,6‐tetramethylpiperidineM metalMCPBA 3‐chloroperoxybenzoic acidMEDAM tetramethyldianisylmethylMEDPM tetramethyldiphenylmethylMEM methoxyethoxymethylMEOX methyl 1‐oxo‐(2‐oxazolidine)‐4‐carboxylateMEPY methyl 2‐oxopyrrolidine‐5‐carboxylateMes mesylMIB morpholino isoborneolMIRC Michael‐initiated ring‐closureMOM methoxymethylMs mesyl (MeSO2)MS molecular sievesMSH O‐mesitylenesulfonylhydroxylamineMTBD 7‐methyl‐1,5,7‐triazabicyclo[4.4.0]dec‐5‐eneMts 2,4,6‐trimethylphenylsulfonylNADH dihydronicotinamide adenine dinucleotideNADPH nicotinamide adenine dinucleotide phosphateNaph naphthylNBS N‐bromosuccinimideNCS N‐chlorosuccinimideNMP N‐methyl pyrrolidinoneNOBIN 1‐amino‐1′‐hydroxylbinaphthylNon nonylNpt naphthylNs nosylNsNIPh [(nosylimino)iodo]benzeneNttl 1,8‐naphthanoyl‐tert‐leucineNu nucleophileOct octylPEG polyethylene glycolPf phenylfluorenylPfm perfluorobutyramidePG protecting groupPhen phenanthrylPhth phthaloylPiv pivaloyl (t‐BuCO)PLA poly‐l‐alaninePLL poly‐l‐leucinePMB 4‐methoxybenzylPMP 4‐methoxyphenylPNB para‐nitrobenzylPNNP N,N′‐bis[o‐(diphenylphosphino)‐benzylidene]cyclohexane‐
1,2‐diaminePPTS pyridinium p‐toluenesulfonatePTAB phenyltrimethylammonium tribromide
List of Abbreviationsxiv
PTC phase‐transfer catalystPTFE polytetrafluoroethylenePy pyridylPybox pyridylbis(oxazoline)r.t. room temperatureSalen salicylidenethanediamineSegphos 5,5′‐bis(diphenylphosphino)‐4,4′‐bi‐1,3‐benzodioxoleSEM 2‐(trimethylsilyl)ethoxymethylSes trimethylsilylethanesulfonylSIPr N,N′‐bis(2,6‐diisopropylphenyl)‐4,5‐dihydroimidazol‐2‐ylideneSMO styrene monooxygenaseSPC sodium percarbonateSu succinimidylTADDOL α,α,α′,α′‐tetraaryl‐1,3‐dioxolan‐4,5‐dimethanolTASF tris(dimethylamino)sulfonium difluorotrimethylsilicateTBAC tetrabutylammonium chlorideTBAF tetrabutylammonium fluorideTBAI tetrabutyl ammonium iodideTBDPS tert‐butyldiphenylsilylTBHP tert‐butyl hydroperoxideTBME tert‐butyl methyl etherTBS tert‐butyldimethylsilylTCPTTL N‐tetrachlorophthaloyl‐(S)‐tert‐leucinateTEA triethylamineTEBAC benzyl triethyl ammonium chlorideTEEDA tetraethylethylene diamineTEMPO 2,2,6,6‐tetramethylpiperidinyloxyTES triethylsilylTf trifluoromethanesulfonylTFA trifluoroacetic acidTHF tetrahydrofuranThio thiopheneTHP tetrahydropyranylTIPS triisopropylsilylTMEDA tetramethylethylenediamineTMG 1,1,3,3‐tetramethylguanidineTMOF trimethylorthoformateTMS trimethylsilylTMSOTf trimethylsilyl trifluoromethanesulfonateTol 4‐methylphenylTON turnover numberTPPP tetraphenylphosphonium monoperoxybisulfateTPS triphenylsilylTr trityl (Ph3C)TRIP 3,3′‐bis‐(2,4,6‐triisopropyl‐phenyl)‐1,1′‐binaphthyl‐2,2′‐diyl
hydrogen phosphateTris 2,4,6‐triisopropylbenzenesulfonyl
List of Abbreviations xv
Troc 2,2,2‐trichloroethoxycarbonylTs tosyl (4‐MePhSO2)UHP urea hydrogen peroxide complexXMO xylene monooxygenaseXyl dimethylphenyl
1
Asymmetric Synthesis of Three-Membered Rings, First Edition. Hélène Pellissier, Alessandra Lattanzi and Renato Dalpozzo. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2017 by Wiley-VCH Verlag GmbH & Co. KGaA
1
1.1 Introduction
Organic chemists have always been fascinated by the cyclopropane subunit [1]. Its strained structure1 and interesting bonding characteristics have attracted the attention of the physical organic community [2]. Due to the limited degrees of freedom, these conformationally constrained molecules have very pronounced steric, stereoelectronic, and directing effects, which make them versatile probes for the study of regio-, diastereo-, and enantioselectivity [3].
On the other hand, the cyclopropane subunit is present in many biologically important compounds including terpenes, pheromones, fatty acid metabolites, and unusual amino acids [1j, 4], and it shows a large spectrum of biological prop-erties, including enzyme inhibition and insecticidal, antifungal, herbicidal, anti-microbial, antibiotic, antibacterial, antitumor, and antiviral activities [5]. This fact has inspired chemists to find novel and diverse approaches to their synthe-sis, and thousands of cyclopropane compounds have been prepared [6]. In particular, naturally occurring cyclopropanes bearing simple or complex func-tionalities are chiral compounds; thus, the cyclopropane motif has long been established as a valuable platform for the development of new asymmetric tech-nologies [7]. The enantioselective synthesis of cyclopropanes has remained a challenge, since it was demonstrated that members of the pyrethroid class of compounds were effective insecticides [8]. Asymmetric synthesis constitutes the main strategy to gain access to enantioenriched compounds, involving the use of either chiral auxiliaries or catalysts that in turn can be metal-centered, small organic asymmetric molecules or enzymes. New and more efficient methods employing all these methodologies to gain enantiomerically enriched cyclopro-panes are still evolving, covering all the main cyclopropanation reactions: those are the well-known Simmons–Smith reaction [9], the transition-metal-catalyzed
Asymmetric Cyclopropanation
1 The strain energy is the difference between the observed heat of formation of a strained molecule and that expected for a strain-free molecule with the same number of atoms.
Asymmetric Synthesis of Three-Membered Rings2
decomposition of diazo compounds [10],2 and the irreversible Michael-initiated ring-closure (MIRC) [11].
1.2 Simmons–Smith Cyclopropanation
In the late 1950s, Simmons and Smith discovered that the reaction of alkenes with diiodomethane in the presence of activated zinc afforded cyclopropanes in high yields [12]. The reactive intermediate is an organozinc species, and the prepara-tion of such species, including RZnCH2I or IZnCH2I compounds and samarium derivatives, was developed in the following years [13]. The popularity of the Simmons–Smith reaction arose from the broad substrate generality, the tolerance of a variety of functional groups, the stereospecificity with respect to the alkene geometry, and the syn-directing and rate-enhancing effect observed with proxi-mal oxygen atoms [14].
In spite of the practical importance of the asymmetric Simmons–Smith cyclo-propanation, the reaction pathway is not completely clear yet [15]. Theoretically, the Simmons–Smith cyclopropanation can proceed via a concerted [2+1] meth-ylene transfer (Scheme 1.1, path A), in which the pseudo-trigonal methylene group of a halomethylzinc halide adds to an alkene π-bond and forms two new carbon─carbon bonds simultaneously, accompanying a 1,2-migration of the hal-ide anion from the carbon to the zinc atom. Alternatively, a [2+2] carbometalla-tion mechanism, in which the halomethyl group and the zinc halide add to both termini of the alkene π-bond followed by intramolecular nucleophilic substitu-tion of the pseudo-carbanion, can be supposed (Scheme 1.1, path B). Experimental studies show that, using a zinc carbenoid, the cyclopropanation very likely pro-ceeds by the [2+1] pathway, primarily because the carbon─zinc bond is covalent and unpolarized. In 2003, Nakamura et al. studied the reaction pathways of cyclopropanation using the Simmons–Smith reagent by means of the B3LYP
2 The high reactivity of diazo compounds counterbalances the ring strain generated in the newly formed cyclopropane unit.
XZnX
H2C CH2
+
Path A
Path B
H H
XXZn
H H
2+
+ ZnX2Methylene transfer
Carbometallation
H H
H H
XZnX 2+
XZnX
XZn
XLA LA
SN2
Scheme 1.1 Possible mechanisms for the Simmons–Smith reaction.
1 Asymmetric Cyclopropanation 3
hybrid density functional method, confirming that the methylene-transfer path-way was the favored reaction course [15]. It took place through two stages, an SN2-like displacement of the leaving group by the olefin, followed by a cleavage of the C─Zn bond to give the cyclopropane ring. However, the alternative carbo-metallation and cyclization pathway was found to be preferred when the carbon─metal bond is more polarized, such as in lithium carbenoids, and this hypothesis has received experimental support [16].
Kinetic studies on the cyclopropanation of dihydropyrroles show an induc-tion period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associ-ated with an underlying Schlenk equilibrium that favors the formation of mon-oalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. Density func-tional theory (DFT) computational studies were also conducted to study the factors influencing reaction rates and diastereoselectivities [17].
1.2.1 Chiral Substrates
The simplest method to obtain chiral compounds is to start from enantiopure substrates, and the built-in chirality is then preserved in the remainder of the reaction sequence. However, this requires the availability of enantiopure sub-stances with the right configuration, and the cheapest ones are amino acids and sugars, which are available in nature as single enantiomers. In the present case, only the cyclopropanation of various asymmetric acyclic allylic alcohols has been widely developed instead, using the heteroatom as the directing group, by chelation with the zinc reagent. Most of them are prepared by enan-tioenriched reduction of unsaturated carbonyl compounds or by cleavage of chiral epoxides. This Simmons–Smith reaction has distinct advantages over the reaction with a simple olefin in relation to the reaction rate and stereocon-trol [18]. Moreover, these reactions have been shown to be much faster than those with simple olefins, and the reaction with a cyclic allylic alcohol took place, forming the cyclopropane ring on the same side as the hydroxyl group [13, 19].
1.2.1.1 Chiral Allylic AlcoholsThe cyclopropanations of 1-cycloalken-3-ols with five-, six-, and seven-membered rings generally produced very good syn:anti ratios, while a reversal of selectivity was observed with larger eight- or nine-membered ring [7a]. This can be explained on the basis of simple conformational analysis of the ground state [20]. For instance, in their approach to enantiomerically pure cyclopropyl ketones, Johnson and Barbachyn showed that β-hydroxysulfoximines derived from cyclic enones could produce the cyclopropane syn to the hydroxy group [21]. In addition, the synthesis of cyclopropanated sugars is diastereoselective. In particular, the syn-isomer was obtained as the major product with halomethylzinc reagents, whereas the anti-isomer could be prepared by a multistep sequence [22].
The stereoselective cyclopropanation of a chiral, acyclic allylic alcohol using the Simmons–Smith reagent (Zn–Cu, CH2I2) was first reported by Pereyre and
Asymmetric Synthesis of Three-Membered Rings4
coworkers in 1978 [23]. They observed that very high syn-selectivity (>200 : 1) was achieved with (Z)-disubstituted olefins, but much lower with (E)-disubstituted olefins (
1 Asymmetric Cyclopropanation 5
fragment of brevipolide H was synthesized by Mohapatra’s group (Scheme 1.6) [29]. More recently, a similar reaction was proposed by Kumaraswamy and cow-orkers, but with inferior results for the synthesis of 11′-epi-brevipolide H [30].
Schmalz’s group developed a fully enantioselective synthesis of a C2-symmetric bicyclo[4.4.1]undecanedione based on a diastereoselective cyclopropanation [31]. It should be noted that the usual Simmons–Smith conditions failed, due to complete decomposition; thus, the desired cyclopropanation was successfully
OGP
OPG1
OH
ZnEt2CH2I2
OGP
OPG1
OH
OO
OH
O
O
O
OMe
Brevipolide H
PG1
95:599:1dr
PG TBSTBDPS
TBS
97Y (%)
PMB
90
Ref 3029
Scheme 1.6 Diastereoselective synthesis of C1–C12 fragment of brevipolide H.
OH
N
O
OMeZnEt2CH2I2
OH
N
O
OMe
H
H
OTBS
TBSO
OO
H
OH
HO
H
C11=S solandelactone EC11=R solandelactone F
11
Scheme 1.5 Key step in the total synthesis of solandelactones E and F.
N
O OHMeO
O
O O
RO OMeOMe
O
O
O
OO
OMeMeOOMe
O
O
R=Me (–)-clavosolide AR=H (–)-clavosolide B
ZnEt2CH2I2
74%92:8 dr
OH
N
OMeO
Scheme 1.4 Key step in the total synthesis of (−)-clavosolide A.
Asymmetric Synthesis of Three-Membered Rings6
achieved using a ZnEt2/ClCH2I reagent, providing the corresponding tricyclic diol as a single diastereomer (Scheme 1.7).
Charette et al. reported that the directed cyclopropanation of chiral acyclic allylic alcohols using gem-dizinc carbenoids was highly stereoselective, yielding either the syn or the anti-cyclopropane, depending upon the substitution pattern of the alkenes [32]. Thus, the zinc cyclopropanation of several cis-disubstituted allylic alcohols occurred with excellent facial selectivity for the attack of the gem-zinc carbenoid, leading to the corresponding syn, cis-cyclopropyl derivatives in high diastereomeric ratios for a wide range of sterically demanding substituents at the allylic position, even with protected allylic alcohol. The zinc cyclopropanation of the corresponding trans-isomer was less stereoselective. However, the intro-duction of a TMS substituent at either the R1 or the R2 position led to the exclusive formation of the anti, cis or of the syn, trans-isomer, as shown in Scheme 1.8.
Occhiato’s group prepared substituted cyclopropane pipecolic acids as confor-mationally restricted templates for linear and cyclic peptidomimetics [33]. The synthesis started from commercially available enantiopure γ-hydroxymethyl-γ-butyrolactones, leading to product with complete stereoselectivity even with remote directing group (Scheme 1.9). It should be noted that, sometimes, the reac-tion conditions deprotected the nitrogen atom, thus avoiding cyclopropanation.
ZnEt2ClCH2I
90%>99% de
OH
OH
OH
OH
O
O
Scheme 1.7 Enantioselective synthesis of a C2-symmetric bicyclo[4.4.1]undecanedione.
BnOOGP
R
1. EtZnI2. ICH(ZnI)2/ZnI23. DCl/D2O or I2
OPG
R
E
H HBnO
syn,cis
58–91%>95:5 dr
BnO
OGPR3R1
R2
1. EtZnI2. ICH(ZnI)2/ZnI23. DCl/D2O or I2
58–91%>95:5 dr
OPG
R3 R3
E
R1 R1
R2
R3R1
R2R3
R1
R2
R2BnO
syn,cis
OPG
E
BnO
syn,transOPG
E
BnO
anti,cis
OPG
E
BnO
PG R1 R2 R3 E Y (%) syn:anti cis:trans H H H Me I 85 60:40 28:72H H H t-Bu D 73 94:6 28:72TIPS H H t-Bu D 64 >95:5 75:25H H TMS Me D 68 95:5H H TMS t-Bu D 77 95:5H TMS H t-Bu D 84 >95:5 95:5
1 Asymmetric Cyclopropanation 7
N CO2MePG
HO ZnEt2CH2I2
Single diastereomer
PG
CO2MeBocCbz
Y (%)
710 (complete deprotection)38 (partial deprotection)
N CO2MePG
HO
N CO2MeCbz
TBSOOH
ZnEt2, CH2I22,4,6-Cl3Ph
86%Single diastereomer N CO2Me
Cbz
TBSOOH
N CO2MeCbz
HOOH
53%Single diastereomer
N CO2MeCbz
HOOH
(eq 1)
(eq 2)
(eq 3)
ZnEt2, CH2I22,4,6-Cl3Ph
Scheme 1.9 Synthesis of substituted cyclopropane pipecolic acids.
1.2.1.2 Chiral Allylic AminesEven though amines have the same potential for binding with the zinc reagent as oxygen functional groups, allylic amines have been much less explored compared to their corresponding alcohols.
Aggarwal and coworkers reported the first highly diastereoselective cyclopro-panation of allylic tertiary amines using the Simmons–Smith reagent [34]. They found a divergent behavior of simple allylic amines and those bearing additional chelating groups. In both cases, the reaction was initiated by complexation of the amine with the zinc reagent. However, in the case of a simple allyl-substituted amine (R = BnCH2, Scheme 1.10, eq 1), this species underwent a 1,2-shift to fur-nish a zinc-complexed ammonium ylide. In the case of an amino alcohol (R = (Ph)CHCH2OH, Scheme 1.10, eq 1), a more stable chelate zinc complex was consid-ered to be formed that did not readily undergo the 1,2-shift. Because of the prox-imity of the olefin to the tightly held zinc carbenoid, however, cyclopropanation occurred instead. On these bases, they used a range of chiral amino alcohols such as phenylglycinol (Scheme 1.10, eq 2), pseudoephedrine (Scheme 1.10, eq 3), and ephedrine (Scheme 1.10, eq 4), to achieve cyclopropanation with very high diastereoselectivity.
1.2.1.3 Chiral Acetal-Directed CyclopropanationsDiastereoselective acetal-directed cyclopropanations constitute the key step of some important natural products or drugs containing cyclopropane moieties. The double asymmetric Simmons–Smith cyclopropanation of the (E)- and (Z)-bis(olefins) could be successfully used to prepare enantioenriched 1,2-bis(2-methylcyclopropyl)ethenes with excellent stereocontrol (Scheme 1.11) [35].
Diastereoselective acetal-directed cyclopropanations also constituted the key step of a total synthesis of solandelactone E (Scheme 1.12, eq 1) [36] and of a total synthesis of a marine fatty acid metabolite having lipoxygenase-inhibiting activ-ity (Scheme 1.12, eq 2) [37], both providing the corresponding cyclopropyl deriv-ative in excellent yield and with high stereoselectivity.
Asymmetric Synthesis of Three-Membered Rings8
Zn(CH2I)2R
N R1R N
R1
ZnI IN
R=(Ph)CHCH2OH
OZn
NPh R1
I
R=BnCH2Ph
R1
ZnIR2Ph
R1
OHR3
Zn(CH2I)2N R2
Ph
R1
OHR3
N
R1=Me, Bn R2=H, Me, Ph, Pr R3=H, Me, Pr
87–96% 92:8 to >98:2 dr
R2
OPGR1 Zn(CH2I)2
N 93–96% 75:25 to >98:2 dr
Ph
R2
OPGR1
N
Ph
PG=H, Me R1=H, Me, Pr R2=Me, Pr, Ph
Ph
OHZn(CH2I)2
N 95% >98:2 de
Ph
Ph
OH
N
Ph
(eq 1)
(eq 2)
(eq 3)
(eq 4)
Scheme 1.10 Cyclopropanation of allylic tertiary amines.
OOZnEt2CH2I289%
Single diastereomer
OO
O OZnEt2CH2I260%
Single diastereomer
O O
Scheme 1.11 Double asymmetric Simmons–Smith cyclopropanation of bis(olefins).
O O
Et2ZnCH2I2
TBDPSO
OO
OTBDPSO
O OH
H
95%Single diastereomer
O
O
EtO2C
Et2ZnCH2I2
72%Single diastereomer
H
H
O
O
EtO2CSolandelactone E(Scheme 1.5)
(eq 1)
(eq 2)
Metabolite
Scheme 1.12 Diastereoselective acetal-directed cyclopropanations.
1 Asymmetric Cyclopropanation 9
Finally, fluorocyclopropanation of trans-styryldioxolane derived from d-glyc-eraldehyde acetonide afforded the desired cyclopropane in 73% yield, in 94 : 6 dr, and with 99% ee, with the fluorine substituent being oriented trans to the diox-olane. The cis-isomer led to a 75 : 25 dr, and the major isomer, isolated in 62% yield and with 99% ee, was found to be the all-cis-fluorocyclopropane [38].
1.2.1.4 Simple Chiral AlkenesIn the absence of a directing group, the cyclopropanation of cyclic olefins is gen-erally subjected to steric effects. The level of stereochemical induction is usually very high, and the sense can be predicted on the basis of the prevailing ground-state conformation of the starting olefin. For instance, a stereoselective cyclopro-panation from the more accessible β-face produced a key intermediate in the synthesis of (+)-acetoxycrenulide, as a single isomer (Scheme 1.13, eq 1) [39]. Another stereoselective cyclopropanation was used by Corey and Lee in their β-amyrin total synthesis (Scheme 1.13, eq 2) [40]. The regioselective methylena-tion of the 17–18 double bond should be also outlined, since the analogous reac-tion using dibromocarbene added exclusively to the 12–13 double bond.
The stereocontrol in the cyclopropanation of acyclic alkenes, in which the basic group that directed the reagent is not on a stereogenic center, usually was not very high, except when the allylic position bore a bulky dimethylphenylsilyl group. In fact, the cyclopropanation of functionalized (E)-crotylsilanes bearing a bis-homoallylic hydroxyl group gave reasonably good diastereoselectivities depending on the nature of the groups on the homoallylic position (the best results are 81% yield and 95 : 5 anti:syn ratio). It is worth noting that AlMe3 was the organometallic species generating the carbenoid, because both the zinc- and samarium-derived reagents failed to produce the desired product [41].
Standard Simmons–Smith conditions were applied by Abad et al. to the cyclo-propanation of a tetracyclic diterpene [42]. The cyclopropanation took place
O
H
HO
TBDPSO
H
O
O
H
HO
TBDPSO
H
OZnEt2CH2I2
92%Single diastereomer
O
OAc
H
O
(+)-Acetoxycrenulide
BzO
H
HBzO
H
H
56%HO
H
H
H
β-Amyrin
(eq 1)
(eq 2)
ZnEt2CH2I2
Scheme 1.13 Cyclopropanation of simple chiral cyclic olefins.
Asymmetric Synthesis of Three-Membered Rings10
stereoselectively from the less hindered β-side of the double bond, affording the expected cyclopropane in excellent yield and diastereoselectivity (Scheme 1.14). This tricyclo[3.2.1.0]octane moiety was a key intermediate in the synthesis of trachylobane-, beyerane-, atisane-, and kaurane-type diterpenes.
Based on the same considerations on the steric effects of bulky polycyclic sys-tems, Tori and coworkers applied standard Simmons–Smith conditions in the last step of a total synthesis of (+)-crispatanolide (Scheme 1.15) [43]. Surprisingly, the major product was not the expected (+)-crispatanolide, but a diastereomer, very likely because of the directing effect of the lactone carbonyl group. However, this synthesis allowed similarly assignment of the absolute configuration to the natural (+)-crispatanolide.
Moreover, 2-azabicyclo[3.1.0]hexane-3-carboxylic acids were obtained from chi-ral 2,3-dihydropyrroles derived from (R)-glutamic acid. The asymmetric Simmons–Smith reaction and hydrolysis reaction mainly led to the all-(R)-product. In this Simmons-Smith reaction the reaction time was found to influence the E/Z ratio and the best ratio was reached after 19.5 h (Scheme 1.16) [44].3
H
O
O
H
O
O
81 : 19
H
O
O
(+)-Crispatanolide
78%+
ZnEt2CH2I2
Scheme 1.15 Last step of a total synthesis of (+)-crispatanolide.
94%Single diastereomer
O
O
H
H
ZnEt2CH2I2 O
O
H
H
Scheme 1.14 Cyclopropanation of a tetracyclic diterpene.
HOOC
HOOCNH2
NBoc
Boc
ZnEt2, CH2ICl
NBoc
Boc
Hydrolysis
86:14 dr 30% overallNHOOC
Boc
Scheme 1.16 Synthesis of 2-azabicyclo[3.1.0]hexane-3-carboxylic acid.
3 The paper has only the abstract in English. There the formation of all-(S)-product is reported, but schemes report unnatural glutamic acid and it is always numbered R#. Sometimes among Chinese characters some products named S# are reported. Perhaps the reaction was performed from both enantiomers of glutamic acid.
1 Asymmetric Cyclopropanation 11
1.2.2 Chiral Auxiliaries
The strategy that uses chiral auxiliaries is based on the transformation into “ chiral product equivalents” by binding an enantiomerically pure derivative to the starting material. These compounds are then stereoselectively transformed into new chiral intermediates that contain new stereogenic centers in high dias-tereomeric excess, with diastereoselectivity being controlled by the presence of the chiral auxiliary fragment. Subsequent cleavage of the chiral auxiliary moiety affords a chiral compound containing a stereogenic center in high enantiomeric excess.4 Thus, a number of auxiliary-based approaches, which can be encom-passed in four general classes, have been reported for the Simmons–Smith cyclo-propanation (Table 1.1). Most of these reactions led to cyclopropylmethanols (Scheme 1.17).
Table 1.1 Chiral auxiliaries for Simmons–Smith reaction using ZnEt2, CH2I2.
Starting material Yield (%) de (%) Product References
Allylic ethers
O
BnO
BnOBnO
OHO
R1
R2
R3
≥95 ≥98 R1
R2
R3
HO
[45]
O OBnOBn
HO
O
R1
R2
R3
≥95 ≥98 R1
R2
R3
HO
[45]
O
BnO
BnOBnO
OH R1
R2
R3
O
83–93 92–94 R1
R2
R3
HO
[46]
OHO
R1
R2
R3
90–98a ≥93 R1
R2
R3
HO
[47]
OO
Ph
BnO
OH
OR1
R3 R2
67–95b Up to 100
R1
R2
R3
HO
[48]
4 The need for additional steps to add and remove the chiral auxiliary reduces the overall yields and leads to wastage of material. However, this strategy was the first used by chemists to obtain enantioenriched products, and only later, the chiral catalysis emerged.
(Continued)
Asymmetric Synthesis of Three-Membered Rings12
Starting material Yield (%) de (%) Product References
Acetals
R2R1
O
OCO2-i-Pr(Et)
CO2-i-Pr(Et)
50–95 93–97
CHOR2
R1 [49]
R2R1
O
O Ar34–67 66–92
CHOR2
R1 [50]
O
OO
OArR1
R2
R3
O
O
45–90 21–81
CHOR2
R1
R3
[51]
O
O
O
H
H
OO
H
H
R3
R2
R3
69–87b 50–100 R1
R2
R3
HO
[52]
OOR1
R2n
BnOOBn 54–99
c 88–95R1
R2n
O [53]
α,β-Unsaturated carbonyl derivatives
CpFe R1
R2O
OC PPh3 49–86d 94–97CO2H
R1
R2
[54]
O
HN
O
Ph
TIPS
62e 99 CO2HPh [55]
TIPSO O
PhNH
56e 99 CO2HPh [55]
Table 1.1 (Continued)
